Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism最新文献

{"title":"Transcriptome analysis reveals sexual disparities in gene expression in rat brain microvessels.","authors":"Partha K Chandra,&nbsp;Sinisa Cikic,&nbsp;Melody C Baddoo,&nbsp;Ibolya Rutkai,&nbsp;Jessie J Guidry,&nbsp;Erik K Flemington,&nbsp;Prasad Vg Katakam,&nbsp;David W Busija","doi":"10.1177/0271678X21999553","DOIUrl":"https://doi.org/10.1177/0271678X21999553","url":null,"abstract":"<p><p>Sex is an important determinant of brain microvessels (MVs) function and susceptibility to cerebrovascular and neurological diseases, but underlying mechanisms are unclear. Using high throughput RNA sequencing analysis, we examined differentially expressed (DE) genes in brain MVs from young, male, and female rats. Bioinformatics analysis of the 23,786 identified genes indicates that 298 (1.2%) genes were DE using False Discovery Rate criteria (FDR; p < 0.05), of which 119 (40%) and 179 (60%) genes were abundantly expressed in male and female MVs, respectively. Nucleic acid binding, enzyme modulator, and transcription factor were the top three DE genes, which were more highly expressed in male than female MVs. Synthesis of glycosylphosphatidylinositol (GPI), biosynthesis of GPI-anchored proteins, steroid and cholesterol synthesis, were the top three significantly enriched canonical pathways in male MVs. In contrast, respiratory chain, ribosome, and 3 ́-UTR-mediated translational regulation were the top three enriched canonical pathways in female MVs. Different gene functions of MVs were validated by proteomic analysis and western blotting. Our novel findings reveal major sex disparities in gene expression and canonical pathways of MVs and these differences provide a foundation to study the underlying mechanisms and consequences of sex-dependent differences in cerebrovascular and other neurological diseases.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2311-2328"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X21999553","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25473943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke.","authors":"Sonia Sanchez-Bezanilla,&nbsp;Rebecca J Hood,&nbsp;Lyndsey E Collins-Praino,&nbsp;Renée J Turner,&nbsp;Frederick R Walker,&nbsp;Michael Nilsson,&nbsp;Lin Kooi Ong","doi":"10.1177/0271678X211005877","DOIUrl":"https://doi.org/10.1177/0271678X211005877","url":null,"abstract":"<p><p>There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2439-2455"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211005877","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25527382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, ¹¹C-GW2580, and ¹¹C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.","authors":"Xiaoyun Zhou,&nbsp;Bin Ji,&nbsp;Chie Seki,&nbsp;Yuji Nagai,&nbsp;Takafumi Minamimoto,&nbsp;Masayuki Fujinaga,&nbsp;Ming-Rong Zhang,&nbsp;Takashi Saito,&nbsp;Takaomi C Saido,&nbsp;Tetsuya Suhara,&nbsp;Yasuyuki Kimura,&nbsp;Makoto Higuchi","doi":"10.1177/0271678X211004146","DOIUrl":"https://doi.org/10.1177/0271678X211004146","url":null,"abstract":"<p><p>Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, ¹¹C-GW2580, and compared it to a reported CSF1R tracer, ¹¹C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic ¹¹C-GW2580- and ¹¹C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of <i>App^{NL-G-F/NL-G-F}</i>-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, ¹¹C-GW2580 captured changes in CSF1R availability more sensitively than ¹¹C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of ¹¹C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of ¹¹C-CPPC. In summary, our results demonstrated that ¹¹C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2410-2422"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211004146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25519809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periinfarct rewiring supports recovery after primary motor cortex stroke.","authors":"Mitsouko van Assche,&nbsp;Elisabeth Dirren,&nbsp;Alexia Bourgeois,&nbsp;Andreas Kleinschmidt,&nbsp;Jonas Richiardi,&nbsp;Emmanuel Carrera","doi":"10.1177/0271678X211002968","DOIUrl":"https://doi.org/10.1177/0271678X211002968","url":null,"abstract":"<p><p>After stroke restricted to the primary motor cortex (M1), it is uncertain whether network reorganization associated with recovery involves the periinfarct or more remote regions. We studied 16 patients with focal M1 stroke and hand paresis. Motor function and resting-state MRI functional connectivity (FC) were assessed at three time points: acute (<10 days), early subacute (3 weeks), and late subacute (3 months). FC correlates of recovery were investigated at three spatial scales, (i) ipsilesional non-infarcted M1, (ii) core motor network (M1, premotor cortex (PMC), supplementary motor area (SMA), and primary somatosensory cortex), and (iii) extended motor network including all regions structurally connected to the upper limb representation of M1. Hand dexterity was impaired only in the acute phase (<i>P</i> = 0.036). At a small spatial scale, clinical recovery was more frequently associated with connections involving ipsilesional non-infarcted M1 (Odds Ratio = 6.29; <i>P =</i> 0.036). At a larger scale, recovery correlated with increased FC strength in the core network compared to the extended motor network (rho = 0.71;<i>P</i> = 0.006). These results suggest that FC changes associated with motor improvement involve the perilesional M1 and do not extend beyond the core motor network. Core motor regions, and more specifically ipsilesional non-infarcted M1, could hence become primary targets for restorative therapies.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2174-2184"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211002968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25521956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke.","authors":"Sicheng Li,&nbsp;Yichen Huang,&nbsp;Yang Liu,&nbsp;Marcelo Rocha,&nbsp;Xiaofan Li,&nbsp;Pengju Wei,&nbsp;Dilidaer Misilimu,&nbsp;Yunhe Luo,&nbsp;Jing Zhao,&nbsp;Yanqin Gao","doi":"10.1177/0271678X21995694","DOIUrl":"https://doi.org/10.1177/0271678X21995694","url":null,"abstract":"<p><p>Lymphocytes play an important role in the immune response after stroke. However, our knowledge of the circulating lymphocytes in ischemic stroke is limited. Herein, we collected the blood samples of clinical ischemic stroke patients to detect the change of lymphocytes from admission to 3 months after ischemic stroke by flow cytometry. A total of 87 healthy controls and 210 patients were enrolled, and the percentages of circulating T cells, CD4⁺ T cells, CD8⁺ T cells, double negative T cells (DNTs), CD4⁺ regulatory T cells (Tregs), CD8⁺ Tregs, B cells and regulatory B cells (Bregs) were measured. Among patients, B cells, Bregs and CD8⁺ Tregs increased significantly, while CD4⁺ Tregs dropped and soon reversed after ischemic stroke. CD4⁺ Tregs, CD8⁺ Tregs, and DNTs also showed high correlations with the infarct volume and neurological scores of patients. Moreover, these lymphocytes enhanced the predictive ability of long-term prognosis of neurological scores when added to basic clinical information. The percentage of CD4⁺ Tregs within lymphocytes showed high correlations with both acute and long-term neurological outcomes, which exhibited a great independent predictive ability. These findings suggest that CD4⁺ Tregs can be a biomarker to predict stroke outcomes and improve existing therapeutic strategies of immunoregulatory lymphocytes.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2280-2294"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X21995694","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25413596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction.","authors":"Kang Huo,&nbsp;Meng Wei,&nbsp;Meng Zhang,&nbsp;Zhanqiang Wang,&nbsp;Peipei Pan,&nbsp;Sonali S Shaligram,&nbsp;Jinhao Huang,&nbsp;Leandro B Do Prado,&nbsp;Julia Wong,&nbsp;Hua Su","doi":"10.1177/0271678X21996177","DOIUrl":"https://doi.org/10.1177/0271678X21996177","url":null,"abstract":"<p><p>Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68⁺ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2162-2173"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X21996177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25413595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior.","authors":"Gianna Huber,&nbsp;Mikolaj Ogrodnik,&nbsp;Jan Wenzel,&nbsp;Ines Stölting,&nbsp;Lukas Huber,&nbsp;Olga Will,&nbsp;Eva Peschke,&nbsp;Urte Matschl,&nbsp;Jan-Bernd Hövener,&nbsp;Markus Schwaninger,&nbsp;Diana Jurk,&nbsp;Walter Raasch","doi":"10.1177/0271678X211003497","DOIUrl":"https://doi.org/10.1177/0271678X211003497","url":null,"abstract":"<p><p>Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer's disease.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2356-2369"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211003497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25488018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep white matter hyperintensity is associated with the dilation of perivascular space.","authors":"Peiyu Huang,&nbsp;Ruiting Zhang,&nbsp;Yeerfan Jiaerken,&nbsp;Shuyue Wang,&nbsp;Wenke Yu,&nbsp;Hui Hong,&nbsp;Chunfeng Lian,&nbsp;Kaicheng Li,&nbsp;Qingze Zeng,&nbsp;Xiao Luo,&nbsp;Xinfeng Yu,&nbsp;Xiaopei Xu,&nbsp;Xiao Wu,&nbsp;Minming Zhang","doi":"10.1177/0271678X211002279","DOIUrl":"https://doi.org/10.1177/0271678X211002279","url":null,"abstract":"<p><p>Understanding the pathophysiology of white matter hyperintensity (WMH) is necessary to reduce its harmfulness. Dilated perivascular space (PVS) had been found related to WMH. In the present study, we aimed to examine the topological connections between WMH and PVS, and to investigate whether increased interstitial fluid mediates the correlation between PVS and WMH volumes. One hundred and thirty-six healthy elder subjects were retrospectively included from a prospectively collected community cohort. Sub-millimeter T2 weighted and FLAIR images were acquired for assessing the association between PVS and WMH. Diffusion tensor imaging and free-water (FW) analytical methods were used to quantify white matter free water content, and to explore whether it mediates the PVS-WMH association. We found that most (89%) of the deep WMH lesions were spatially connected with PVS, exhibiting several interesting topological types. PVS and WMH volumes were also significantly correlated (r = 0.222, p < 0.001). FW mediated this association in the whole sample (β = 0.069, p = 0.037) and in subjects with relatively high WMH load (β = 0.118, p = 0.006). These findings suggest a tight association between PVS dilation and WMH formation, which might be linked by the impaired glymphatic drainage function and accumulated local interstitial fluid.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2370-2380"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211002279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25521959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-dimensional ultrastructure of the brain pericyte-endothelial interface.","authors":"Sharon Ornelas,&nbsp;Andrée-Anne Berthiaume,&nbsp;Stephanie K Bonney,&nbsp;Vanessa Coelho-Santos,&nbsp;Robert G Underly,&nbsp;Anna Kremer,&nbsp;Christopher J Guérin,&nbsp;Saskia Lippens,&nbsp;Andy Y Shih","doi":"10.1177/0271678X211012836","DOIUrl":"https://doi.org/10.1177/0271678X211012836","url":null,"abstract":"<p><p>Pericytes and endothelial cells share membranous interdigitations called \"peg-and-socket\" interactions that facilitate their adhesion and biochemical crosstalk during vascular homeostasis. However, the morphology and distribution of these ultrastructures have remained elusive. Using a combination of 3D electron microscopy techniques, we examined peg-and-socket interactions in mouse brain capillaries. We found that pegs extending from pericytes to endothelial cells were morphologically diverse, exhibiting claw-like morphologies at the edge of the cell and bouton-shaped swellings away from the edge. Reciprocal endothelial pegs projecting into pericytes were less abundant and appeared as larger columnar protuberances. A large-scale 3D EM data set revealed enrichment of both pericyte and endothelial pegs around pericyte somata. The ratio of pericyte versus endothelial pegs was conserved among the pericytes examined, but total peg abundance was heterogeneous across cells. These data show considerable investment between pericytes and endothelial cells, and provide morphological evidence for pericyte somata as sites of enriched physical and biochemical interaction.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2185-2200"},"PeriodicalIF":6.3,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X211012836","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38886294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice.","authors":"Sevda Lule,&nbsp;Limin Wu,&nbsp;Aliyah Sarro-Schwartz,&nbsp;William J Edmiston,&nbsp;Saef Izzy,&nbsp;Tanya Songtachalert,&nbsp;So Hee Ahn,&nbsp;Neil D Fernandes,&nbsp;Gina Jin,&nbsp;Joon Yong Chung,&nbsp;Siddharth Balachandran,&nbsp;Eng H Lo,&nbsp;David Kaplan,&nbsp;Alexei Degterev,&nbsp;Michael J Whalen","doi":"10.1177/0271678X20973609","DOIUrl":"https://doi.org/10.1177/0271678X20973609","url":null,"abstract":"<p><p>Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead (<i>RIPK1^D138N/D138N</i>) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL (<i>Mlkl^-/-</i>) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.</p>","PeriodicalId":520660,"journal":{"name":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1623-1633"},"PeriodicalIF":6.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0271678X20973609","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38618653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}